Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Abstract

CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer1,2,3. Generating effective CD8+ T cell–mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen4. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor α chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.

Cite this article

Teague, R., Sather, B., Sacks, J. et al. Interleukin-15 rescues tolerant CD8⁺ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12, 335–341 (2006). https://doi.org/10.1038/nm1359

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